GlaxoSmithKline's Avandamet

According to the National Diabetes
Information Clearinghouse, 20.8 million
people in the United States have diabetes,
which accounts for $132 billion in
medical costs each year.1,2

Approximately 90% of people with diabetes
in North America are classified as
having type 2 diabetes mellitus (DM).1
These patients typically are treated with
one or more oral hypoglycemic medications
rather than with insulin. On July 11,
2006, GlaxoSmithKline announced the
approval of Avandamet as first-line therapy
to control glucose levels in patients
diagnosed with type 2 DM when dual
therapy is needed.3,4

Pharmacology

Avandamet (rosiglitazone maleate and
metformin HCl) is a combination of 2 oral
hypoglycemic agents consisting of a thiazolidine
and a biguanide, respectively.
The advantage of Avandamet lies within
the additive effect of 2 different mechanisms
of action. Rosiglitazone targets
insulin resistance and decreases circulating
insulin levels, whereas metformin reduces
glucose production at the hepatic
level.5 The metabolic processes also differ
because rosiglitazone is primarily
metabolized by the CYP450 isoenzyme
2C8 (2C9 minor) and metformin is primarily
metabolized renally.5

Clinical Trials

A 32-week, randomized, double-blind
trial to evaluate the efficacy and safety of
Avandamet, compared with rosiglitazone
and metformin as single agents, confirmed
Avandamet's superiority in
glycemic control over the 2 monotherapies.4 The inclusion criteria required
patients with type 2 diabetes who were
drug-naive. The study defined drug-naive
as not having taken an oral hypoglycemic
medication or insulin for more than 15
days within the 12 previous weeks.4

This study evaluated 468 patients
between the ages of 18 and 70 years. The
Avandamet treatment arm included a
starting total daily dose of 2 mg/500 mg.
The investigators were allowed to
increase doses in increments of 2 mg/500 mg, with a maximum daily dose of
8 mg/2000 mg.4 Patients in the rosiglitazone
arm were initiated at a total
daily dose of 4 mg and could be titrated
up to 8 mg. Those in the metformin treatment
arm started at a 500-mg total daily
dose, with a maximum dose of 2000 mg
(titrated in increments of 500 mg).4

When test results were compared with
baseline, the researchers found that
Avandamet was superior to metformin
and rosiglitazone in reducing hemoglobin
A1C and fasting plasma glucose (FPG).

A second study was an open-label,
single-arm, 24-week trial to evaluate the
safety and efficacy of Avandamet in 120
drug-naive patients with type 2 diabetes.
The inclusion/exclusion criteria were
similar to those of the aforementioned
32-week trial, except that this open-label
study included patients with A1C
>11% or FPG >270 mg/dL.4 The Avandamet
regimen included a starting dose
of 4 mg/1000 mg, with the possibility of
a dose increase to 6 mg/1500 mg at 4
weeks. The maximum dose allowed was
8 mg/2000 mg.4 The results showed that
Avandamet reduced A1C by 4% and FPG
by 139 mg/dL from baseline.4,5

Safety

The most common adverse events
observed in the trials were nausea, vomiting,
diarrhea, headache, and dyspepsia.4
An increase in weight also was reported.
Avandamet is contraindicated in patients
with renal dysfunction.5 A black-box
warning has been issued for the risk of
lactic acidosis due to the accumulation of
metformin.5 Lactic acidosis is a rare but
serious side effect; 50% of the cases are
fatal. Rosiglitazone can cause edema,
which can lead to or exacerbate heart
failure. Avandamet is not recommended
for patients in New York Heart Association
Class III and IV because of an
increased risk of cardiovascular events.5

Conclusion

It is important for patients with type 2
DM to have adequate glucose control.
Nonpharmacologic treatment includes
caloric restriction, weight loss, and exercise.
It also is important for patients to be
compliant with their medications and
with routine doctor visits.

The total daily dose of Avandamet usually
is prescribed in divided doses that are
taken with meals to reduce gastrointestinal
side effects.5 Alcohol should be avoided
when taking Avandamet.5 Avandamet
is available in the following strengths:
1 mg/500 mg, 2 mg/500 mg, 4 mg/500
mg, 2 mg/1000 mg, and 4 mg/1000 mg
rosiglitazone/metformin, respectively.